A lay summary by Harry McDonough, reviewed by Ian Coldicot and by an MND lay panel.

Background

Motor neurone disease (MND) is a progressive and disabling condition of the nervous system with no current cure. Faced with this diagnosis and outlook, it might be expected that the mood and emotional wellbeing of people living with MND could be affected.

Whilst each individual will process and respond to their MND diagnosis in their own way, some may have more persistent psychological difficulty. Depression is a condition in which there is a persistent change in mood, where individuals may feel sad, anxious, worthless, or lose interest in things previously enjoyed.

Why is the study important?

It is currently uncertain how common depression is in MND. This would be useful and important information for:

• MND sufferers and their loved ones – to be aware of the signs of depression and discuss with healthcare professionals as needed

• Healthcare professionals – to know whether to routinely assess for depression and, if required, offer treatment

• Planning clinical services – to ensure psychological services are available and accessible for people with MND

What did the authors do and how did they do it?

This study aimed to determine how common depression is in MND. The study was part of a wider national study called TONiC (Trajectories of Outcome in Neurological Conditions). TONiC looks at the factors that influence quality of life for people with neurological conditions, including MND.

People living with MND were recruited to the TONiC study. To best determine how common depression was in the group studied, the authors identified cases of depression in multiple ways:

• Modified-Hospital Anxiety Depression scale (M-HADS-D): a questionnaire commonly used to assess individuals for depression

• Medications taken by people with MND: was the individual already prescribed an antidepressant medication?

• Questionnaire of past medical history: this asked individuals if they had already been diagnosed with depression in the past

The researchers also looked at how depression symptoms changed over a period of 2.5 years in the group recruited to the study. To do this, they used computer modelling techniques to identify groups of individuals that followed similar trajectories of depressive symptoms over time.

What are the results?

Depression was found in 23% of the 1120 people living with MND recruited into the study. On average, those with depression were more likely to be younger and have more advanced MND than those without depression. Females were more likely to have depression than males and those with depression reported a worse level of quality of life in comparison to those without depression. The presence of depression did not, however, seem related to how long an individual had had MND.

Depression was more common in people with MND if they

• Were young

• Were female

• Had more advanced MND

The authors looked at when people were diagnosed with depression in relation to their MND diagnosis. They found 23% were diagnosed with depression at the time of or following their MND diagnosis. 5% reported their depression began more than 3 years prior to their MND diagnosis, with the remaining 72% being affected in the 3 years leading up to their MND diagnosis.

The authors studied whether those identified as having depression were on antidepressant medication. They found that 82% of people with MND with depression were on antidepressant medication. Those not on medication were much more likely to be male and at an advanced stage of MND.

The study aimed to categorise people with MND into groups based on their trajectories of depressive symptoms over time. Doing this, the authors found that people fell into 3 different groups. As they studied the groups over time throughout the study, they saw that the level of depressive symptoms stayed stable in each group. The table above describes that depression was more common in people with MND if they were female, young, or had advanced MND.

What do the findings mean going forward for people with the disease?

The study estimates that 23% of people living with MND have depression. Given how common depression would appear to be, the authors suggest MND clinics should routinely and proactively assess people for depression, exploring treatment options, including ready access to psychology services.

Nearly three-quarters of depression cases in people with MND start less than 3 years before MND diagnosis. With this in mind, the authors suggest that depression may be an early feature of MND before the more widely recognised symptoms start. Indeed, depression has been recognised as an early symptom in other neurological conditions, such as multiple sclerosis. It is, however, worth remembering that more than 75% of people with MND in this study did not have depression. Therefore, if depression is an early symptom of MND, it does not appear to be the case for everyone.

Looking to areas for future research, the authors suggest it is important to consider undertaking a trial of treatments of depression symptoms in MND. This study shows that depression is common in people with MND, affects quality of life, yet the effects of treatments for depression in MND are not yet known.

This study can be found at:
https://www.tandfonline.com/doi/pdf/10.1080/21678421.2022.2096410?casa_token=SfHRxtDNXmQAAAAA:PyXfSYlAsuV8oe0Xghl4bTOrq5935CLRxIqwVQTrHKDc9TVzBpo-oaiEjqjr38ZFAI23ReHDOS582Q

Paper title
Prevalence of depression in amyotrophic lateral sclerosis / motor neuron disease: multi-attribute ascertainment and trajectories over 30 months

Author list
C. A. Young, J. Ealing, C. J. McDermott, T. L. Williams, A. Al-Chalabi, T. Majeed, K. Talbot, T. Harrower, C. Faull, A. Malaspina, J. Annadale, R. J. Mills, A. Tennant & On Behalf Of The Tonic Study Group

Publication details including date of publication

Journal: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Year: 2023

How common is depression in motor neurone disease? - Readable Research 

Lay summary by Louise Heywood, reviewed by Dr Tom Payne, and by a Parkinson’s Disease Lay Panel.

Background

Mitochondria act as the batteries of the cell, producing high amounts of energy for cells to function properly. In Parkinson’s, these batteries produce less energy, resulting in brain cells starving and dying. Therefore, one hope to slow down the progression of Parkinson’s is to use medication to keep mitochondria healthy. Ursodeoxycholic acid (UDCA) is commonly used as a treatment for liver disease, making it an ideal candidate for drug repurposing – using existing drugs to treat different conditions. This study was a Phase II clinical trial, where patients were randomly assigned to either UDCA treatment or a placebo drug, with neither participants nor doctors knowing which participants were taking UDCA. The study took place across two centres, one at Sheffield Teaching Hospitals (STH) and one at University College London (UCL) Hospitals. All participants had been diagnosed with Parkinson’s for less than three years.

Why is the study important?

There are currently no approved treatments for Parkinson’s that can prevent the loss of affected brain cells nor alter the progression of the condition – the available treatments can help reduce symptoms, but not the underlying causes. UDCA is a potential ‘neuroprotective’ drug that is hoped can prevent further loss of brain cells, and as such, represents an important step forward in the treatment of Parkinson’s. The first step to getting a new treatment to patients is to assess its safety and efficacy in clinical trials.

What did the authors do and how did they do it?

The trial consisted of 31 total participants randomly assigned to either UDCA treatment or placebo group with 20 taking UDCA and 10 taking a placebo. Participants remained on the treatments for 48 weeks, followed by an 8-week ‘wash-out’ period where treatment was stopped, to assess the longevity of UDCAs effects.

The main assessments were regarding safety and tolerability, but the study also looked at the effects of UDCA on the brain, and on Parkinson’s movement symptoms. To confirm that UDCA was having an effect on the brain a type of brain scan known as phosphorus-31 magnetic resonance spectroscopy was used. This is a specific brain scan that can measure the changes in levels of energy in the brain. Changes in movement symptoms were assessed using the standard clinical rating scale (MDP-UPDRS-III) and a digital, wearable, sensor-based system (Sheffield cohort only).

What are the results?

One participant completely withdrew from the study, due to problems swallowing, the high number of capsules, and was subsequently replaced. Another two participants stopped taking their tablets early, but still completed the study. This was due to the burden of taking so many capsules in addition to their existing medication. There were two serious adverse events during the trial, both of which affected the same patient in the placebo group, and in total 24 adverse reactions in 14/31 participants, affecting 10 UDCA participants and 4 placebo participants. The most frequently reported side effects of UDCA were mild diarrhoea and mild nausea, which required no treatment and was of short (24-72 hr) duration, therefore the authors felt that the 30 mg/kg dose of UDCA daily was well-tolerated and safe.

The brain scans of participants taking UDCA showed that there was a potentially increased efficiency of energy breakdown in the brains of UDCA participants, suggesting that UDCA is having a positive effect on Parkinson’s. The sensor-based movement analysis showed that participants taking UDCA had an increase in steps per minute when walking, and a reduction in time taken to make a full stride, and the time stood on both feet while walking when compared to those taking placebo. All of this would tentatively suggest an improvement in walking ability in the UDCA group, however the small number of participants means that the results must be approached with caution. However, the MDP-UPDRS-III clinical rating scale showed that both those taking UDCA and placebo experienced an improvement in their Parkinson’s symptoms during the study.

The study also looked at effects of UDCA on non-motor symptoms, such as depression; on a depression rating scale (MADRS), scores showed a small but important increase in the UDCA group, compared to the placebo group, though scores were overall still far below the cut off that indicates depression.

What do the findings mean going forward for people with the disease?

The study shows an improvement, or comparatively slower decline, in walking ability in the UDCA group, in addition to a slower progression of movement symptoms on the standard rating scale, suggesting UDCA has potential as a new Parkinson’s drug. Though the results of this study seem promising for the safety of UDCA, which was its primary aim, the study is limited by its small number of participants, and therefore a larger trial is needed to confirm whether UDCA can slow down the progression of Parkinson’s.

This study can be found at
Wiley Online Library DOI: 10.1002/mds.29450

Paper title
A Double-Blind, Randomised, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson’s Disease

Author list
Payne, T., Appleby, M., Buckley, E., van Gelder, L. M. A., Mullish, B. H., Sassani, M., Dunning, M. J., Hernandez, D., Scholz, S. W., McNeill, A., Libri, V., Moll, S., Marchesi, J. R., Taylor, R., Su, L., Mazza, C., Jenkins, T. M., Foltynie, T. and Bandmann, O.

Publication details including date of publication.
Movement Disorders, Published May 2023

Clinical trial results for UDCA as a new drug for Parkinson’s Disease - Readable Research 

Lay summary by Rhiannon Brown, reviewed by Dr Tom Payne & a Parkinson’s disease lay panel

Background

Parkinson’s Disease involves the progressive loss of brain cells that leads to symptoms such as muscle stiffness, tremors and difficulty walking. It is unclear why people with Parkinson’s lose these brain cells, but we know that two tiny cell components, called mitochondria and lysosomes, are commonly affected. Mitochondria act as batteries to provide the energy that cells need to survive; lysosomes recycle damaged parts of cells (including damaged mitochondria) so that they can stay healthy. Lots of previous research has shown that in Parkinson’s Disease, the mitochondria and the lysosomes are not working correctly, which may contribute to the development of Parkinson’s.

Why is the study important?

There are over 135,000 people with Parkinson’s in the UK (Parkinson’s UK, 2023) and each person with Parkinson’s is unique. This could be through the specific problem in the brain cells causing their Parkinson’s, the symptoms they experience, or how their condition progresses over time. This means that it is very hard to find a cure that works for everyone. Consequently, many researchers are looking for similarities between people so they can group those with similar versions of the disease into smaller and more treatable groups.

One possible way that people can be grouped is by the type and extent of damage to their mitochondria and lysosomes. However, it is difficult to investigate the condition of mitochondria and lysosomes as they are very small and located inside the body, therefore it is important to trial different methods to find the best approach.

What did the authors do and how did they do it?

The authors took 35 people with Parkinson’s and 25 healthy people without Parkinson’s and compared two methods for assessing the number and function of the mitochondria and lysosomes, in order to evaluate the potential use of these methods for grouping patients. The two methods are as follows:

1. A small amount of the person’s skin was taken from their forearm and grown in a lab for multiple weeks until lots of skin cells were present. The cells were then analysed using advanced microscopes.

2. Images of two areas of the brain affected in Parkinson’s were recorded using a specialised MRI scanning technique. Rather than using it to produce images of the brain (the most common use of MRI scanners in clinical practice) they used a different technique to measure how well the brain cells produced energy (which reflects how well the mitochondria are working: more energy = better mitochondria).

What are the results?

The results from both methods showed that the number and function of the mitochondria and lysosomes can be both greatly increased or decreased in people with Parkinson’s. This contrasts with the results for healthy people which are much more similar to each other. This agrees with previous research that different people with Parkinson’s have different amounts and type of damage to their mitochondria and lysosomes and therefore it is feasible to group them into smaller, more similar groups. This could be advantageous for finding specific and more personalised treatments. Both methods showed similar results, however the brain imaging approach (method two) is a lot easier and quicker and therefore more likely to be of use in situations when people need grouping quickly, such as in clinical trials.

What do the findings mean going forward for people with the disease?

The findings add further evidence that people with Parkinson’s can have varying and different problems in their cells which reinforces the need for grouping them when investigating new drugs. For example, some people with Parkinson’s possess a larger number of mitochondria and lysosomes, however they are damaged and do not work very well. These people would likely not benefit from a drug that increases the number of mitochondria or lysosomes but instead would need a drug that can improve their function. Testing a specific drug on a targeted group of people with Parkinson’s, could increase the likelihood of positive outcomes in clinical trials and new drugs being approved for use.

This study can be found at
https://doi.org/10.1093/brain/awad364

Paper title
Multimodal assessment of mitochondrial function in Parkinson’s disease

Lead Authors
Thomas Payne, Heather Mortiboys, Oliver Bandmann

Publication details including date of publication
Brain, Volume 147, Issue 1, January 2024.

Using two methods to investigate damaged mitochondria in Parkinson’s Disease - Readable Research 

Lay summary by David O’Brien, reviewed by Ian Coldicott and an MND lay panel

Background

Motor neuron disease (MND) causes damage to the nerves controlling muscles involved in movement, speech, swallowing and breathing. There is currently no cure, so the main focus is on treating the symptoms of MND and maintaining quality of life. MND affects both physical and mental wellbeing, and we know that depression, anxiety and fear are common in those who have MND. We also know that people with MND might benefit from psychological support to cope with such a devastating diagnosis, and adapt to their condition as it progresses over time.

Acceptance and Commitment Therapy (ACT) is a psychological therapy that involves acceptance of the condition, mindfulness, motivation, and behaviour change techniques. These allow the individual to live their life in a meaningful way despite their worries, fears and negative thoughts. ACT has already been shown to be beneficial for improving quality of life and mental wellbeing in other long-term health conditions, including muscle diseases and chronic pain. This large study involving 16 centres in the UK has found that ACT improves quality of life for people living with MND.

Why is the study important?

This is the first major clinical trial showing that a psychological therapy can be beneficial for improving quality of life and wellbeing in MND. The next steps will be to translate the benefit from this study into real-world quality of life benefits for people living with MND.

What did the authors do and how did they do it?

• This study was a type of clinical trial called a randomised controlled trial (RCT). This is considered the best way of working out if an intervention (like a drug, a device, or a psychological therapy, for instance) is really effective.

• Half the participants are randomly selected to receive the intervention (in this case Acceptance and Commitment Therapy) alongside their usual MND care, while half receive their usual MND care but do not receive the additional intervention. Sometimes a placebo, or dummy intervention, is used but this can be difficult when assessing interventions other than drugs.

• In this study, 97 participants received ACT in addition to their usual MND care and 94 received their usual care alone. 93 caregivers were also interviewed to assess the effect of ACT on carer burden, which is the physical and psychological strain on caregivers of someone with MND. Roughly half the caregivers involved were carers of a participant in the ACT group.

• The ACT group received up to 8 one-to-one sessions with a trained therapist, each lasting up to 1 hour, over 4 months. Around 1 in 10 of the included participants reported depression and 2 in 10 reported anxiety at the beginning of the study. The majority did not report any psychological problems.

• The study team assessed the participant’s change in overall quality of life, as well as changes in depression, anxiety and caregiver burden. These were assessed at 6 months and 9 months after entry into the study..

What are the results?

The participants who received ACT in addition to their usual care reported a better overall quality of life, when this was assessed using the McGill Quality of Life Questionnaire (a common quality of life questionnaire used in research that asks questions about physical, psychological, emotional and existential wellbeing) after 6 months and 9 months. They also had a significantly lower level of depression on average, and fewer participants in the ACT group developed depression compared with the usual care group. Statistical tests showed that this effect is likely to be meaningful for people with MND. There were no significant changes in the levels of carer burden between the two groups.

Around 8 in 10 participants in the ACT group were satisfied with this intervention, and around 7 in 10 attended all 8 sessions. There were no serious negative effects associated with ACT. The majority of ACT sessions were delivered by video call, which is more inclusive for many people with MND who live remotely or struggle to attend a face to face appointment.

What do the findings mean going forward for people with the disease?

Following the evidence that ACT can improve quality of life and mental wellbeing in people with MND, there will be a good case for providing this therapy as part of routine care. This will take some time, as it will require the necessary training and funding to be provided so that MND centres can deliver this. There are plans to develop an online self-help version of ACT to allow more people access to this intervention. It may be that some individuals benefit from ACT more than others, and this may be explored in future studies.

This study can be found at
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00533-6/fulltext  

Paper title
Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK 

Lead Authors
Rebecca L. Gould, Christopher J. McDermott,…, on behalf of the COMMEND Collaboration Group 

Publication details including date of publication
Lancet 2024; 403: 2381–94 Published Online May 9, 2024 https://doi.org/10.1016/ S0140-6736(24)00533-6 

Trial indicates psychological therapy can improve quality of life for people living with MND - Readable Research 

Lay summary by Dr Andrew Strange and reviewed by Dr Scott Allen, Dr Naomi Hartopp and an MND & Dementia lay panel.

Background

Previous research on a type of dementia called frontotemporal dementia (FTD), which affects the frontal and temporal parts of the brain (Figure 1), mainly focused on the inherited form, which accounts for about 30% of cases and is linked to specific gene (part of the DNA that encodes proteins and is passed from person to person) mutations. However, the sporadic form (sFTD), where no previous family history exists, makes up roughly 70% of cases, and has been less studied genetically. This study aimed to address that gap by examining the entire genome (all the DNA) to find common genetic variations associated with sFTD.

Figure 1. Side picture of the brain showing the Frontal (blue) and Temporal (green) lobes. Created in BioRender.com.

Why is the study important?

This study both identifies a new risk gene for sFTD, but also confirms some previous work on 2 genes (MAPT and APOE). This study also looks at the genetics of different European populations and finds important differences between them, which must be taken into consideration in future work.

What did the authors do and how did they do it?

The researchers carried out a large genetic study to find genes linked to sFTD, a form of dementia that occurs without a family history.

They collected DNA samples from 5,651 people with sFTD and 16,821 controls across Europe and grouped the participants as either Central/Nordic or Mediterranean Europeans based on their genetic code. By comparing genetic differences between sFTD and control groups, they aimed to identify gene alterations linked to sFTD, and if there were differences across the 2 geographic groupings.

The primary tool used in this study was a Genome-Wide Association Study (GWAS), where researchers look at the difference between the genetic makeup of individuals to see if there are any similarities between predefined groups. GWAS typically use many thousands of people to identify complex genetic difference between different groups.

What are the results?

The researchers discovered that certain genes increase the risk of developing sFTD.

Two genes, namely MAPT and APOE, had already been tentatively identified in other work as being risk genes, and this study also confirmed them to be associated with a higher risk of developing sFTD. A risk gene, as the name implies, is associated with the risk of developing a given disorder, but is far from being a simple black and white determinant. Additionally, a new gene, RPSA-MOBP, was identified as carrying significant risk of sFTD.

The effect of the APOE gene was stronger in people from the Mediterranean, indicating that genetic risk can vary among populations. Additionally, the researchers found that sFTD shares genetic links with other neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS/MND), progressive supranuclear palsy, and corticobasal degeneration. This implies that these conditions might share common biological mechanisms or pathways.

Understanding these shared genetic factors could be crucial for uncovering how these diseases develop and for finding potential treatments that could address multiple disorders.

What do the findings mean going forward for people with the disease?

These findings could lead to earlier diagnosis of sFTD through genetic testing, helping individuals receive timely care and better manage the disease.

Understanding the specific genes involved may also pave the way for new treatments that target these genetic factors, potentially slowing down or altering the progression of the disease.

Moreover, recognizing that sFTD shares genetic links with other neurodegenerative conditions could facilitate broader research efforts and therapeutic strategies that benefit multiple diseases.

However, having these genetic variations doesn’t guarantee someone will develop sFTD; it simply increases the risk.

This study can be found at
https://doi.org/10.1016/j.ajhg.2024.05.017

Paper title
Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Lead author
Claudia Manzoni, Valentina Escott-Price

Publication details including date of publication
American Journal of Human Genetics, July 11 2024

Investigating the genetics of frontotemporal dementia with no family history - Readable Research 

Lay summary by Dr Andrew Strange, reviewed by Dr Naomi Hartopp & a Parkinson’s disease lay panel

Background

Mobility issues affect individuals with a range of conditions, from neurological conditions such as Parkinson’s disease to physical injuries and heart disease. Mobility issues impact quality of life, leading to a higher risk of falls, loss of independence, and reduced physical fitness. Accurately measuring mobility in real-world settings (such as in the person’s home, not in a hospital) is crucial for understanding the effectiveness of interventions aimed at improving gait and overall mobility.

Monitoring these mobility issues has been challenging. Currently, there is a range of different computer programs (referred to as algorithms) which are run on wearable devices aimed at tracking a patient’s gait at home. These wearable devices help doctors and researchers better understand how an individual’s mobility may be affected, allowing the development of new treatments. Since the use of these devices are still new, it has been unclear which algorithm works best for patients in their own homes. This study aimed to assess several available algorithms to determine which is the best for detecting how patients walk at home.

Why is the study important?

This study is particularly important because it tests a range of algorithms in the patients’ home environment and real-world settings, not just within a hospital. Traditional clinical assessments often lack real-world validity as they are performed in controlled environments, where patients walk very differently. High quality monitoring devices, with good algorithms can provide continuous and accurate measurements of how a person walks in everyday settings, leading to better insights into mobility-affecting disorders.

What did the authors do and how did they do it?

The authors recruited 108 participants, including 20 healthy older adults and individuals with one of six conditions: Parkinson’s disease, multiple sclerosis, hip fractures, chronic obstructive pulmonary disease, and heart failure. This group represents a wide range of different mobility issues to test the devices. Participants used a wearable device to monitor their gait. Each algorithm was tested over 2.5 hours, during which participants were asked to go about their day as normal and perform specific tasks such as going up stairs. The collected data were compared against a previously established gold-standard reference known as Inertial Modules, Distance Sensors, and Pressure Insoles (INDIP). A total of 14 different algorithms were compared to INDIP, across measurements covering the different movements that make up a person’s walking gait. These measurements included stride length and speed, how good the algorithm was at detecting when walking started and stopped or when a patient initially placed their foot on the floor. How a patient performs the actions as part of walking is very informative about how their particular condition is progressing, so accurate monitoring of them is vitally important.

What are the results?

The research team identified that the best algorithm varied depending on the condition, but that the best algorithm for a condition was often still quite effective when used on participants with other conditions. Walking speed significantly affected algorithm effectiveness: walking speeds below 0.5 m/s, the boundary between “slow” and “medium” walking speeds, caused almost all of the tested algorithms to become less accurate. Since condition heavily affected walking speed, the best algorithm for each condition varied. The most challenging group was the fracture group, which tended to have a very slow, irregular gait.

What do the findings mean going forward for people with the disease?

Having assessed a number of different algorithms across various measurements, for each measurement one algorithm outperformed the others and whilst there was no one single perfect option for all conditions, there was a clear best choice for therapists and clinicians depending on the presented condition. This will allow much more accurate monitoring of patients, aiding the development of treatment plans and tracking disease progression.

This study can be found at
Journal of NeuroEngineering and Rehabilitation

Paper title
Assessing real-world gait with digital technology? Validation, insights, and recommendations from the Mobilise-D consortium

Lead Authors
M. Encarna Micó-Amigo,  Silvia Del Din

Publication details including date of publication
Journal of NeuroEngineering and Rehabilitation, 14 June 2023.

Finding your feet: Tracking natural gait in those living with mobility-affecting disorders - Readable Research 

Lay summary by Sophie Voase, reviewed by Dr Laura Evans

Background

Multiple sclerosis (MS) is a chronic disease which affects the central nervous system (made up of the brain and spinal cord). In MS, the immune system attacks the myelin sheath, the protective layer which surrounds neurons (the nerve cells that carry messages from different parts of the central nervous system and to the muscles that enable voluntary movement). This process is called demyelination and these repeated bouts of inflammation injure the neurons over time. This compromises the ability of these neurons to carry messages and leads to MS symptoms. These symptoms are different depending on which part of the central nervous system is affected. There are different types of MS and the type of MS a person has depends on the course of MS. The type of MS that this paper focuses on is relapsing MS which is the most common form. In this form, the person with MS develops new symptoms, called a relapse, followed by a recovery period. Not all these symptoms get better, and this can lead to disability getting worse after each relapse.

Why is the study important?

One of the focuses of treatment is on finding ‘disease-modifying treatments’ (DMT). This means finding a medication which aims to reduce the number of relapses a person with MS will have, protect the neurons and slow down the rate of progression of disability, not just treat the symptoms. When a new DMT is being developed, it is important to measure a) whether it works and b) assess whether it is safe. In a clinical trial participants are assigned to different medications or to a placebo at random (called a randomised placebo-controlled trial). The aim is to compare how effective and safe these medications are. After the clinical trial is finished, there can be a period called an ‘open label extension’ in which the medication is trialled for a longer period with all participants on the active medication in order to look at how safe and effective it is when it is taken for longer.

Ofatumumab is a medication which is given via an injection under the skin every four weeks (subcutaneous injection). It works on reducing the amount of one of the immune system cells called a B cell. The idea is that if you reduce how active the immune system is, you can reduce how much the immune system attacks the neurons. Four different clinical trials were carried out looking at how effective Ofatumumab is and how best to give the medication. Ofatumumab showed promising results in these clinical trials and was approved by the FDA for multiple sclerosis in 2020, and in Europe and the UK in 2021. Ofatumumab was shown to reduce annual relapse rates and had a lower number of people with worsening disability when compared to an oral DMT and compared with the placebo. As ofatumumab is given via an injection under the skin, reactions both throughout the body and at the injection site must be considered. After the initial clinical trial period had finished, the person with MS could choose to enter the open label extension period. This study is important as it reports the findings of the open-label extension from the four different clinical trials looking at the safety of ofatumumab up to a maximum of four years. This means that there are many people involved which means that people have more confidence in the safety of the medication.

What did the authors do and how did they do it?

The authors followed up with 1703 people continuing ofatumumab from four different clinical trials in an open label extension study called ALITHIOS, summarised in the diagram below.

There were eight main types of side effects, or adverse reactions that emerged from the clinical trials. The authors collected information on reactions which were thought to be related to the injection of ofatumumab (called injection-related reactions). These reactions then further analysed:

1. What type of reaction was it?

• Reaction involving the whole body (systemic injection-related reaction)

• Reaction at the site of the injection (local-site injection-related reactions)

2. How severe was the reaction?

• Mild

• Moderate

• Severe

• Life-threatening

3. How long after the person had the injection did they develop the reaction?

4. What number ofatumumab injection did the reaction happen with?

5. Was there anything else that was more likely to have caused the reported reaction?

• If yes, that case was removed from the analysis.

What are the results?

Almost a quarter of people had at least one systemic reaction to an injection over the whole period; these happened more commonly the first time they received ofatumumab. Almost all the reactions were classed as mild/moderate and non-serious. The three most common symptoms reported were fever, headache and chills. Only five people needed to stop receiving ofatumumab due to a reaction. There were no life-threatening reactions to ofatumumab during the four years. Some people received steroids, or non-steroidal anti-inflammatory medications before their injections but this had no effect on how many had a reaction or the severity of the reaction.

1 in 10 people had a local site reaction following an injection; almost all were mild/moderate and non-serious. None were life threatening and only one person stopped ofatumumab due to a local site reaction. The most common local site reactions were redness and pain.

What do the findings mean going forward for people with the disease?

This study has demonstrated that ofatumumab is generally well-tolerated over time. When reactions occurred, they were mainly mild and happened after the first injection. As medication side effects are one of the main reasons for switching disease-modifying treatments, this means that ofatumumab might be a good option for people with MS. Ofatumumab can be injected monthly and does not need to be given into a vein like other medications which require a cannula to be inserted. Therefore, people could self-inject at home which would reduce the amount of hospital visits needed.

This study can be found at
https://journals.sagepub.com/doi/10.1177/20552173231203816 

Paper title
Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis

Lead Authors
John Kramer and Patrick Vermersch

Publication details including date of publication
Published in Multiple Sclerosis Journal – Experimental, Translational and Clinical on the 10th October 2023.

Assessing the impact of a drug to slow down progression of relapsing multiple sclerosis - Readable Research 

Lay summary by Justine Salumbides, reviewed by Prof Alison Condliffe

Background

Human immunodeficiency virus type 1 (HIV-1) is the virus which causes Acquired Immune Deficiency Syndrome (AIDS).

This virus infects and depletes or exhausts a range of immune cells which lead to a range of other potentially life-threatening infections. Amongst the immune cell ‘victims’, HIV-1 can impair the development and function of natural killer (NK) cells, which are important in controlling a wide range of viruses. Due to these defects, the immune response to viruses, in this case HIV, is impaired. NK cells play an important role in the immune response because their activation is essential for optimising antiviral responses. For example, activation of NK cells leads to the production of antiviral chemicals like interferon-gamma (IFN-γ). IFN-γ production is a process that requires energy and is mostly produced in structures called mitochondria, which act as cellular ‘generators’. These metabolic processes and their effects are induced by very common viruses such as cytomegalovirus (CMV).

CMV causes few or only mild symptoms in healthy people, who develop super-charged or ‘adaptive’ NK cells following CMV infection. However, HIV-1 infected individuals experience major problems with CMV infection because their immune system is already experiencing many immune challenges, suggesting their NK cells are not undergoing appropriate metabolic changes to develop into efficient cellular killers.

Why is the study important?

The study provides a better understanding of how HIV-1 infection reduces the ability of NK cells to fight infection, which has not previously been explored. It investigates how HIV-1 affects metabolism to impair the way NK cells generate their energy and how this might impact their ability to fight HIV-1 and other viruses. By understanding what factors and pathways are affected in the metabolic challenges that NK cells undergo, it could provide an opportunity to find new ways to improve the immune function and reduce severity of infections in people with HIV-1.

What did the authors do and how did they do it?

The study included a range of methods to investigate the metabolic function of NK cells:

• Patients: Blood samples were collected from people with HIV (patients) and without HIV (controls), all of whom had previously been infected with CMV.

• Identifying types of NK cells: Distinctive proteins on the surface of cells allowed different types of NK cells to be identified. These proteins also show how super-charged or adaptive the NK cells are.

• Structure and function of NK cells: A microscope was used to acquire detailed pictures of NK cells to analyse the size and shape of the mitochondria (the cellular ‘generators’ which produce most of the cell’s energy). To understand the function of NK cells, experiments were conducted to identify which chemical processes are used by NK cells to produce energy. To do so, ‘metabolic inhibitors’ (range of chemicals that interfere with metabolism) were used to understand how HIV-1 affects cellular energy production and prevents full NK activation when it is needed.

Together, these methods provided a comprehensive understanding of the metabolic and functional characteristics of NK cells in the context of HIV-1 infection by comparing results between the HIV-1 positive patients and the HIV-1 negative controls.

What are the results?

HIV-1 affects the structure and function of the mitochondria: It was found that the mitochondria in NK cells from HIV-1 positive patients were much smaller and rounder than those seen in healthy NK cells, suggesting they had partly disintegrated. They also had changes in their surrounding membrane, suggesting they were not very healthy. 

HIV-1 affects the metabolism of NK cells: NK cells from HIV-1 positive patients were found to have greatly reduced mitochondrial energy production compared to the HIV-1 negative individuals. Adaptive NK cells which play an important role in fighting infections, were found to be greatly affected by HIV-1 infection. 

IL-15 enhances NK cell function: IL-15 is a protein that is involved in activating key immune cells including NK cells. It was found that treating NK-cells with IL-15 could compensate for the metabolic impairments found in NK cells during HIV-1 infection. By enhancing NK cell function with the use of IL-15, metabolic activity was re-regulated and the production of IFN-γ was enhanced even in the presence of HIV-1.

What do the findings mean going forward for people with the disease?

By having a better understanding of how NK cells produce energy and how HIV-1 infection may impair these processes, the development of new treatments to improve the immune response to HIV-1 infection becomes more promising. This study highlights that IL-15 could play an important role in reducing the effects that HIV-1 presents on NK cells. This is because IL-15 shows signs of being able to restore NK cell metabolism and function to enhance the immune response to HIV-1 infection.

This study can be found at
https://doi.org/10.1172/jci.insight.173099

Paper title
IL-15 reprogramming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Lead author
Elia Moreno-Cubero and Dimitra Peppa

Publication details including date of publication
JCI Insight. 2024;9(4):e173099.

Revitalising ‘exhausted’ immune cells in HIV-1 infection - Readable Research 

Lay summary by Dr Sophie Voase and reviewed by Dr Laura Evans and an MND lay panel.

Background

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neurone disease (MND) which causes progressive weakness leading to problems walking, eating, and breathing leading to death from respiratory failure for most patients within 3 years from symptom onset.

Frontotemporal dementia (FTD) is a rare form of dementia which can cause behavioural changes and problems with language amongst other symptoms. Both ALS and FTD are neurodegenerative diseases which means that there is death of nerve cells (neurons) in key areas of the brain and spinal cord. This death of neurons leads to the symptoms that people with ALS/FTD experience. Research has shown that a change in a gene, C9orf72, is likely responsible for 1 in 10 cases of ALS and FTD in people of European descent.

The changes in the C9orf72 gene cause both loss of normal function effects for the gene and actively toxic effects to occur, both of which are not fully understood yet, and this makes developing targeted treatments challenging. In addition, some people with changes in C9orf72 develop ALS/FTD much earlier than others which suggests that there are other factors influencing the development of ALS/FTD rather than it being the result of a single gene. For the majority of patients with ALS, no single genetic cause can be identified but a combination of other genetic factors or an interaction of genetic and environmental factors are thought to determine the risk for ALS, so some of these genetic factors could influence the age of disease onset in C9orf72 cases as well.

One method of identifying possible treatments is testing drugs against a single biological target, for example a gene. However, this method fails to consider the wider picture which is that many genes interact and influence each other within the body and can explain why some promising treatments do not show any positive effect on humans during clinical trials. The field of genomics, which involves the study of all of the genes in an individual and how they interact, offers a more powerful method in the study of disease biology and drug development.

Why is the study important?

This study demonstrates the value of using large-scale genomic databases from thousands of patient and control samples to unravel complex disease biology and discover new drug targets. It showed how changes in one gene, C9orf72, interact with other genes to influence the age of onset of ALS/FTD.

The study also highlighted cell pathways which C9orf72 is involved with and then used this information to screen existing medications which might delay the onset of disease in people with changes in C9orf72 by targeting the whole pathways rather than an individual gene. This study focused on using existing medications already approved for use in humans.

This approach, called drug repurposing, makes the time to clinical use much quicker if found effective than developing a completely new medication as its safety in humans is already known. Furthermore, crucially, the evidence of the drug modifying the gene pathway through hitting its target means a clinical trial would be more likely to succeed.

What did the authors do and how did they do it?

There were three main stages in this study (see diagram). During the first stage, the authors compared the entire genetic material of each person (called their genome) in people with ALS, both with and without a change in the C9orf72 gene, to the genomes of healthy volunteers. This served two purposes: the first was to calculate a genetic risk score to predict how likely a person is to develop ALS based on their genetics and the second was to identify if this general ALS risk score had an effect on the age of onset of ALS/FTD in people with the change in the C9orf72 gene.

In the second stage, the authors identified which processes/pathways these ALS risk genes were involved in and existing drugs which would target these pathways.

In the third stage, the authors reprogrammed stem cells donated by people with C9orf72-related ALS and also healthy volunteers, into a type of nerve cell called a motor neuron and applied the chosen drug treatments to test for protective effects.

What are the results?

Genetic Risk Score

Through comparison of the general ALS genetic risk score to people with changes in the C9orf72 gene, the authors found that there were sixteen gene changes which were responsible for developing symptoms at a younger age in C9orf72-related ALS/FTD.

Pathways and Drug Identification

Further examination of what functions these sixteen gene changes are related to within the body showed that they were involved in the internal cellular scaffolding giving structure to cells including nerve cells and the pathways involved in the movement of substances around within cells along this scaffolding. Through matching of pathways and genes to existing drugs, the authors found three drugs which were able to reverse some of the effects of the ALS risk genes. Two of these drugs had side effects which might be harmful in people with ALS. Therefore, this left one drug, acamprosate, a medicine used to maintain alcohol abstinence, to go forward to testing in the C9orf72 patient cell models stage.

Cell Models

The authors tested acamprosate on the motor neurons that they had developed from stem cells from people with C9orf72-related ALS and compared them to those from healthy volunteers. They found that the drug reduced the number of C9orf72-motor neurons which died. This protective effect was comparable to that of riluzole (a medication currently used to prolong survival in people with ALS). Acamprosate did not have any harmful effects on the motor neurons.

What do the findings mean going forward for people with the disease?

This study is important because it offers some explanation for why people with the change in the C9orf72 gene develop ALS/FTD at such varying ages. It may also indicate the possible pathways which are involved in influencing age of onset and some early evidence that these pathways could be modified to delay disease onset. Although this study was preliminary and conducted using cells only, the known safety of acamprosate and the strong biological rationale for its use in ALS demonstrated in this paper could lead to it being considered for testing in people with C9orf72-related ALS/FTD. Further work should also be done to see whether acamprosate could have a positive effect on the wider ALS population who do not have changes in the C9orf72 gene.

This study can be found at
www.sciencedirect.com/science/article/pii/S2666979X24002982?via%3Dihub

Paper title
Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data

Lead author
Sara Saez-Atienzar and Bryan J. Traynor

Publication details including date of publication
Published in Cell Genomics on 21/10/2024

Lay summary by Emmanuel Firima and reviewed by Dr Scott Allen.

Background

The way SARS-CoV-2 (the virus responsible for the COVID-19 pandemic) causes brain disease has puzzled researchers. When COVID first started, it left many infected people with neurological complications. While a lot of such complications were considered mild for example headache, researchers observed that some people came down with more serious complications like seizures and stroke. Different study approaches suggested that direct infection of the brain by the virus was unlikely the cause of neurological symptoms. In fact, the virus and antibodies against it were hardly seen in the cerebrospinal fluid (which cushions the brain and spinal cord). It therefore appears that SARS-CoV-2 affects the brain indirectly likely through its effects on inflammation, the immune system and changes within the brain’s blood vessels.

When the body is attacked by bugs, it produces cells like neutrophils and T-cells (types of blood cells that fight infections) and substances like interleukins as part of an immune response. Scientists can measure the concentration of these cells and interleukins to identify an ongoing immune response or inflammation. Sometimes, organ-specific markers are produced which indicate that a particular organ has been injured. In patients infected with COVID-19, increased levels of interleukin-6 in the blood and cerebrospinal fluid have been associated with meningitis, stroke, cognitive and memory problems- regardless of the severity of respiratory disease. Studies showed that brain-specific injury markers were increased in COVID-19 and reflected the severity of the disease. Still, the relationship between the immune system and markers of brain injury remains a unclear.

Why is the study important?

This study sheds light on the relationship between mediators of immune response and markers of brain injury, and neurological complications. It helps us to know if, among patients with COVID-19, levels of brain injury markers increase or decrease as immune mediators increase or decrease- that is if they are correlated.

What did the authors do and how did they do it?

The researchers studied two large groups of COVID-19 positive patients in different centres. Blood samples were collected from these patients when they first became ill (acute phase), as well as during early and late phases of recovery. From these samples, the authors measured markers of brain injury, mediators of inflammation and antibodies, and investigated any link with the Glasgow Coma Scale (GCS) score of patients during the acute phase. GCS is a tool which helps determine if a patient is conscious- low scores indicate that the patient is losing consciousness. The researchers also sought to establish any link between the level of markers of brain injury, mediators of inflammation and antibodies, and the presence of neurological complications due to COVID-19 in recovering patients. Samples from uninfected individuals were also collected for comparison.

What are the results?

1. COVID-19 raises markers of brain injury among participants with low GCS score. First, comparing healthy individuals to patients with COVID-19, the researchers found that markers of brain injury were substantially higher in patients with COVID-19. Patients with low GCS scores had even higher levels of brain injury markers compared to patients with normal GCS scores.

2. Markers of brain injury remain raised during recovery phases in patients who had a neurological complication of COVID-19. Patients who had neurological complications due to COVID-19 were compared with patients without neurological complications. Of particular interest were early recovery phase (less than six weeks after hospital admission) and late recovery phase (more than six weeks after hospital admission). In the first six weeks, all patients with COVID-19 had raised markers of brain injury. However, these markers remained raised beyond six weeks only among patients who had neurological complications due to COVID-19.

3. Markers of brain injury, as evidence of neurological complication, are associated with levels of mediators of inflammation during the acute phase of COVID-19 infection. The researchers found that among patients with low GCS scores in whom markers of brain injury were raised, mediators of inflammation were also raised. This suggests that activation of inflammation was related to markers of neurological damage.

4. Mediators of inflammation were not raised during late phases after COVID-19. When measured during the recovery phases, the authors found that mediators of inflammation were lower compared to their levels during the acute phase of the illness. This result did not change whether patients had neurological complications or not. And though some markers of brain injury remained elevated during late COVID-19 recovery phases, they were no longer related to levels of mediators of inflammation.

What do the findings mean going forward for people with the disease?

This study demonstrates the complex relationship between mediators of inflammation and markers of brain injury in patients with COVID-19 with or without neurological complications. The authors also showed how markers of brain injury were higher among patients with neurological complications during the acute phase of the infection and remained elevated during the recovery phase after mediators of inflammation had reduced. The relatedness of markers of brain injury and disorganised immune responses may present potential treatment targets for patients with COVID-19.

This study can be found at
https://www.nature.com/articles/s41467-023-42320-4 

Paper title
Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Lead author
Benedict D. Michael and David K. Menon

Publication details including date of publication
Nature Communications 14, 8487 (Dec 2023)